CN108586377A - A kind of preparation method of 3- morpholones - Google Patents
A kind of preparation method of 3- morpholones Download PDFInfo
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- CN108586377A CN108586377A CN201810581339.3A CN201810581339A CN108586377A CN 108586377 A CN108586377 A CN 108586377A CN 201810581339 A CN201810581339 A CN 201810581339A CN 108586377 A CN108586377 A CN 108586377A
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- VEUUMBGHMNQHGO-UHFFFAOYSA-N CCOC(CCl)=O Chemical compound CCOC(CCl)=O VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- OOCYVJHEZIBCHJ-UHFFFAOYSA-N CCOC(COCCNC)=O Chemical compound CCOC(COCCNC)=O OOCYVJHEZIBCHJ-UHFFFAOYSA-N 0.000 description 1
- FGQBGDBLZZPFCM-UHFFFAOYSA-N CN(CCOC1)C1=O Chemical compound CN(CCOC1)C1=O FGQBGDBLZZPFCM-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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Abstract
The present invention provides a kind of preparation methods of 3 morpholone, dehydrohalogenation under the conditions of by 2 halogenated ethamine halogen acid salts existing for organic solvent, amine ester exchange reaction is carried out after gained reaction system is mixed with 2 glycolic acid esters, obtains 2 (2 hydroxyl acetamido) halogen ethane；Ring closure reaction is carried out under the conditions of by described 2 (2 hydroxyl acetamido) halogen ethane existing for base reagent and organic solvent, obtains 3 morpholones.Method and process side reaction provided by the invention is few, is convenient for product purification；It is easy to operate, safe, environmental-friendly；Raw material are easy to get, are cheap；Product yield high (up to 75.5%), purity are high (up to 99% or more), are suitable for industrialized mass production, have good industrial prospect.
Description
Technical field
The present invention relates to medicine intermediate material prepared technology fields, and in particular to a kind of preparation method of 3- morpholones.
Background technology
Razaxaban (Rivaroxaban), the entitled chloro- nitrogen-of 5- ((the 5S) -2- oxygen -3- [- 4- (3- oxygen -4- morpholines of chemistry
Base) phenyl] -1,3- oxazolidine -5- bases -2- thiophene-carboxylic acid amides, trade name visits auspicious appropriate (Xarelto), is by Bayer A.G
With a kind of novel oral anticoagulation Xa factor drug of Johnson Co. cooperative research and development, 2008 first in Canada
City is mainly used for preventing and treating various thrombotic diseases, such as prevents adult patient and selects a time hip joint or knee prosthesis
The formation of postoperative pulmonary embolism (PE) and deep vein thrombosis (DVT) is one of current most promising antithrombotic reagent.
3- morpholones are the critical materials for preparing razaxaban.Currently, 3- morpholones have following several preparation methods：
(1) using morpholine as raw material, the oxidation generation 3- morpholones under potassium permanganate effect (reaction process is as follows).
This method step is few, easy to operate, and raw material is easy to get；But the polyoxy by-product of a series of complex is generated when potassium permanganate oxidation,
It is difficult to purify, and yield is very low, only only 17%.The a large amount of dark brown wastewater treatment of oxidation generation is extremely difficult, causes
Serious environmental pollution.It is only limitted to laboratory lab scale in this way, does not have industrial-scale production future.
(2) it using 2- ethylaminoethanols and chloracetyl chloride as raw material, is reacted under conditions of sodium hydroxide is alkali, it is chloro- to generate 2-
N- (2- ethoxys) acetamide, then (reaction process is such as anti-raw intramolecular cyclization generation 3- morpholones under the action of sodium ethoxide
Shown in lower).But the same side reaction of this method is more, yield is low, and mass production is difficult.
(3) it using 2- ethylaminoethanols and 2- ethyl chloroacetates as raw material, under the action of sodium hydride or metallic sodium, firstly generates
Then amine transesterification ring closure reaction occurs for 2- amine ethoxy ethyl acetates, generates 3- morpholones (reaction process is as follows).But
Sodium hydride or metallic sodium need to be used by being this method, and reaction is violent and sends out a large amount of hydrogen, is very easy to burning, explosion, technique
There are major safety risks, it is also difficult to industrialized mass production.
Invention content
The purpose of the present invention is to provide a kind of preparation method of 3- morpholones, method and process side reactions provided by the invention
Less, safe, product yield and purity are high, are suitable for industrialized mass production.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：
The present invention provides a kind of preparation methods of 3- morpholones, include the following steps：
(1) dehydrohalogenation under the conditions of by the halogenated ethamine halogen acid salts of 2- existing for organic solvent, by gained reactant
System carries out amine ester exchange reaction after being mixed with 2- glycolic acid esters, obtains 2- (glycolamide base) halogen ethane；
(2) by 2- (glycolamide base) halogen ethane item existing for base reagent and organic solvent in the step (1)
Ring closure reaction is carried out under part, obtains 3- morpholones.
Preferably, the molar ratio of the halogenated ethamine halogen acid salts of 2- and 2- glycolic acid esters is 1 in the step (1)：(1~
3)。
Preferably, the halogenated ethamine halogen acid salts of 2- include 2-chloroethyl amine hydrochloride or 2- bromine ethamine hydrogen in the step (1)
Bromate.
Preferably, 2- glycolic acid esters include 2- hydroxy methyl acetates, 2- hydroxyl ethyl acetates, 2- in the step (1)
Hydroxyacetic acid n-propyl or 2- hydroxyacetic acid isopropyl esters.
Preferably, the temperature of amine ester exchange reaction is -10~50 DEG C in the step (1), and the time is 8~10h.
Preferably, the molar ratio of 2- (glycolamide base) halogen ethane and base reagent is 1 in the step (2)：(1~3).
Preferably, base reagent is organic base or inorganic base in the step (2).
Preferably, the organic base includes sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium or the tert-butyl alcohol
Magnesium.
Preferably, the inorganic base includes potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide
Or lithium hydroxide.
Preferably, the temperature of ring closure reaction is 50~100 DEG C in the step (2), and the time is 10~30h.
The present invention provides a kind of preparation methods of 3- morpholones, and the halogenated ethamine halogen acid salts of 2- are existed in organic solvent
Under conditions of dehydrohalogenation, after gained reaction system is mixed with 2- glycolic acid esters carry out amine ester exchange reaction, obtain 2-
(glycolamide base) halogen ethane；By the 2- (glycolamide base) halogen ethane condition existing for base reagent and organic solvent
Lower carry out ring closure reaction, obtains 3- morpholones.Method and process side reaction provided by the invention is few, is convenient for product purification；Operation letter
It is single, safe, environmental-friendly；Raw material are easy to get, are cheap；Product yield high (up to 75.5%), purity it is high (up to 99% with
On), it is suitable for industrialized mass production, there is good industrial prospect.
Specific implementation mode
The present invention provides a kind of preparation methods of 3- morpholones, include the following steps：
(1) dehydrohalogenation under the conditions of by the halogenated ethamine halogen acid salts of 2- existing for organic solvent, by gained reactant
System carries out amine ester exchange reaction after being mixed with 2- glycolic acid esters, obtains 2- (glycolamide base) halogen ethane；
(2) by 2- (glycolamide base) halogen ethane item existing for base reagent and organic solvent in the step (1)
Ring closure reaction is carried out under part, obtains 3- morpholones.
The present invention by the halogenated ethamine halogen acid salts of 2- existing for organic solvent under the conditions of dehydrohalogenation, gained is reacted
System carries out amine ester exchange reaction after being mixed with 2- glycolic acid esters, obtains 2- (glycolamide base) halogen ethane.
In the present invention, the halogenated ethamine halogen acid salts of the 2- preferably include 2-chloroethyl amine hydrochloride or 2- bromine ethamine hydrogen bromines
Hydrochlorate.In the present invention, organic solvent used by the dehydrohalogenation preferably includes dichloromethane, toluene, methanol, ethyl alcohol
Or isopropanol.The present invention does not have the usage amount of the organic solvent special restriction, can be by the halogenated ethamine hydrogen of the 2-
The smooth dehydrohalogenation of halate.In the present invention, the reaction of the dehydrohalogenation is exothermic reaction, anti-in order to neutralize
Heat release is answered, prevents reaction excessively fierce, the halogenated ethamine halogen acid salts of the 2- are preferably stirred by the present invention with organic solvent
Afterwards, ice-water bath is cooled to 10~15 DEG C, is added sodium hydroxide is added portionwise under nitrogen protection, control system temperature is not higher than 20
℃；After sodium hydroxide adds, 25~35min is stirred, the reaction of dehydrohalogenation is completed.The present invention is for the hydroxide
The addition of sodium and the number being added portionwise do not have special restriction, can ensure the halogenated ethamine halogen acid salts of the 2-
Smooth dehydrohalogenation.
In the present invention, the reactant containing halogenated ethamine is obtained after the halogenated ethamine halogen acid salt dehydrohalogenations of the 2-
It is anti-to carry out follow-up amine transesterification without carrying out any post-processing for system, the reaction system after directly being mixed with 2- glycolic acid esters
It answers.In the present invention, the halogenated ethamine is easy oxidation deterioration, unstable, by the salt-forming compound of the halogenated ethamine, i.e. 2-
Halogenated ethamine halogen acid salt is to ensure being smoothed out for the amine ester exchange reaction as initial reaction raw material.
In the present invention, 2- glycolic acid esters preferably include 2- hydroxy methyl acetates, 2- hydroxyl ethyl acetates, 2- hydroxyl second
Sour n-propyl or 2- hydroxyacetic acid isopropyl esters, more preferably 2- hydroxyl ethyl acetates.In the present invention, the halogenated ethamine hydrogen of the 2-
The molar ratio of halate and 2- glycolic acid esters is preferably 1：(1~3), more preferably 1：(1.5~2.5).
In the present invention, gained reaction system and the mixing of 2- glycolic acid esters are preferably the 2- after dehydrohalogenation
Glycolic acid esters are added in gained reaction system, and the feed postition of the 2- glycolic acid esters is preferably added dropwise；The present invention couple
There is no special restriction in the rate of the dropwise addition, using drop rate well known to those skilled in the art.
In the present invention, preferably -10~50 DEG C of the temperature of the amine ester exchange reaction, more preferably -5~30 DEG C, most
Preferably 0~15 DEG C；In an embodiment of the present invention, the amine transesterification preferably carries out at room temperature, that is, is not necessarily to additional add
Heat or cooling.In the present invention, the time of the amine ester exchange reaction is preferably 8~10h；In the present invention, by the 2- hydroxyls
Yl acetate is added in gained reaction system and proceeds by the amine ester exchange reaction, amine ester exchange reaction of the present invention
Time be specifically with 2- glycolic acid esters be added after start timing.The present invention preferably confirms the amine ester by GC detections
Whether exchange reaction is complete；In an embodiment of the present invention, specifically, being to slough halogen by detecting the halogenated ethamine halogen acid salts of 2-
Change the halogenated ethamine obtained after hydrogen and confirms whether the amine ester exchange reaction is complete.
After completing the amine ester exchange reaction, gained system is preferably filtered by the present invention, the filter that will be obtained using water
Liquid is washed, and is isolated the water phase in resulting material after washing, is extracted to gained water phase using dichloromethane, by gained
Organic phase is dried with anhydrous sodium sulfate, after vacuum distillation removal solvent, obtains 2- (glycolamide base) halogen ethane.
In the present invention, the reaction system obtained after the amine ester exchange reaction is direct after simple post-processing obtains crude product
Follow-up ring closure reaction is carried out, without carrying out polishing purification, the production process of product is effectively simplified, improves production efficiency.
In an embodiment of the present invention, the halogenated ethamine halogen acid salts of the 2- are specially 2-chloroethyl amine hydrochloride or 2- bromine second
Amine hydrobromate, the 2- glycolic acid esters are specially 2- hydroxyl ethyl acetates, and reaction equation is as follows：
Wherein, X=Cl or Br.
After obtaining 2- (glycolamide base) halogen ethane, the present invention tries the 2- (glycolamide base) halogen ethane in alkali
Ring closure reaction is carried out under the conditions of agent and organic solvent are existing, obtains 3- morpholones.In the present invention, 2- (the 2- hydroxyl acetyl
Amido) molar ratio of halogen ethane and base reagent is preferably 1：(1~3), more preferably 1：(1.5~2.5).The present invention is for described
The type of base reagent does not have special restriction, using organic base well known to those skilled in the art or inorganic base；In this hair
In bright, the organic base preferably includes sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium or tert-butyl alcohol magnesium, institute
It states inorganic base and preferably includes potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide or lithium hydroxide.
In the present invention, the organic solvent preferably includes ethyl alcohol, isopropanol or tetrahydrofuran.Use of the present invention for the organic solvent
The not special restriction of amount, can be such that the ring closure reaction is smoothed out.
In the present invention, the temperature of the ring closure reaction is preferably 50~100 DEG C, more preferably 65~85 DEG C；In this hair
In bright embodiment, the ring closure reaction is specifically carried out under the reflux temperature of the organic solvent.The present invention is for heating
Heating rate to the temperature of the ring closure reaction does not have special restriction, using heating rate well known to those skilled in the art
.In the present invention, the time of the ring closure reaction is preferably 10~30h, more preferably 15~25h；In the reality of the present invention
It applies in example, specifically to start timing after being warming up to the temperature of the ring closure reaction.
After completing the ring closure reaction, gained system is preferably filtered by the present invention, and filtrate decompression distillation removal is molten
Agent, be heated to reflux after residue is mixed with ethyl acetate, activated carbon 25~35min carry out adsorption bleaching, by resulting material into
Row filtering removal activated carbon and remaining inorganic salts, gained liquid material are mixed with petroleum ether, under 0~5 DEG C, stirring condition
5~7h of recrystallization is carried out, filters, gained filter cake is dried in vacuo, 3- morpholones are obtained.The present invention is dry for the vacuum
Dry condition does not have special restriction, using vacuum drying condition well known to those skilled in the art.
In an embodiment of the present invention, 2- (glycolamide base) the halogen ethane is specially 2- (glycolamide base) chlorine
Ethane or 2- (glycolamide base) bromoethane, reaction equation are following (base reagent is by taking NaOH as an example)：
Wherein, X=Cl or Br.
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.It is aobvious
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
Embodiment 1
2-chloroethyl amine hydrochloride 116g (1.0mol) and dichloromethane 300mL is stirred, ice-water bath cools down 10 DEG C, nitrogen
It is added under gas shielded and 40g sodium hydroxides (1.0mol) is added portionwise, control system temperature is not higher than 20 DEG C, finishes, and stirs 30min
Dehydrochlorination；2- hydroxyl ethyl acetates 114.5g (1.1mol), drop are added dropwise into reaction system of the gained containing 2-chloroethyl amine
Finish, reacts 9h at room temperature, GC detects 2-chloroethyl amine, and the reaction was complete；Gained system is filtered, will be obtained using 100mL water
Filtrate is washed, and is isolated the water phase in resulting material after washing, is extracted to gained water phase using 100mL dichloromethane
It takes, gained organic phase is dried with anhydrous sodium sulfate, after vacuum distillation removal solvent, obtain 2- (glycolamide base) chloroethene
Alkane.
The 2- (glycolamide base) chloroethanes, isopropanol 800mL are mixed with sodium hydroxide 60g (1.5mol), delayed
Slow to be heated to reflux (80~85 DEG C), gained system is filtered by insulation reaction 12h, and filtrate decompression is distilled removal solvent,
Be heated to reflux after residue is mixed with 300mL ethyl acetate, 5g activated carbons 30min carry out adsorption bleaching, by resulting material into
Row filtering removal activated carbon and remaining inorganic salts, gained liquid material are mixed with 200mL petroleum ethers, in 0 DEG C, stirring condition
Under carry out recrystallization 6h, a large amount of solids are precipitated, filter, gained filter cake is dried in vacuo, white powder 3- morpholones are obtained
76.3g, yield 75.5%, purity 99.3%；Fusing point is 97~99 DEG C.
1H-NMR(400MHz,CDCl3)δ:7.886(s,1H)；4.098(s,1H)；3.770 (t, J=10.4Hz, 2H)；
3.371~3.357 (m, 2H)；13C-NMR(100MHz,CDCl3):δ:169.488；67.583；63.093；41.094；IR
(neat)1667,1347,1120,799cm-1。
Embodiment 2
2-chloroethyl amine bromate 205g (1.0mol) and dichloromethane 800mL is stirred, ice-water bath cools down 15 DEG C, nitrogen
It is added under gas shielded and 138.2g potassium carbonate (1.0mol) is added portionwise, control system temperature is not higher than 20 DEG C, finishes, and stirs
30min sloughs hydrogen bromide；2- hydroxyl ethyl acetates 156g (1.5mol) is added dropwise into reaction system of the gained containing 2- bromine ethamine,
Drop finishes, and reacts 9h at room temperature, GC detects 2- bromines ethamine, and the reaction was complete；Gained system is filtered, will be obtained using 200mL water
Filtrate washed, isolate the water phase in resulting material after washing, gained water phase extracted using 150mL dichloromethane
It takes, gained organic phase is dried with anhydrous sodium sulfate, after vacuum distillation removal solvent, obtain 2- (glycolamide base) bromine second
Alkane.
The 2- (glycolamide base) bromoethane, ethyl alcohol 500mL are mixed with potassium hydroxide 67.3g (1.2mol), delayed
Slow to be heated to reflux (75~80 DEG C), gained system is filtered by insulation reaction 10h, and filtrate decompression is distilled removal solvent,
Be heated to reflux after residue is mixed with 300mL ethyl acetate, 5g activated carbons 30min carry out adsorption bleaching, by resulting material into
Row filtering removal activated carbon and remaining inorganic salts, gained liquid material are mixed with 200mL petroleum ethers, in 5 DEG C, stirring condition
Under carry out recrystallization 6h, a large amount of solids are precipitated, filter, gained filter cake is dried in vacuo, white powder 3- morpholones are obtained
68.8g, yield 68.1%, purity 99.2%；Fusing point is 97~99 DEG C.
1H-NMR(400MHz,CDCl3)δ:7.886(s,1H)；4.098(s,1H)；3.770 (t, J=10.4Hz, 2H)；
3.371~3.357 (m, 2H)；13C-NMR(100MHz,CDCl3):δ:169.488；67.583；63.093；41.094；IR
(neat)1667,1347,1120,799cm-1。
Embodiment 3
2-chloroethyl amine hydrochloride 116g (1.0mol) and dichloromethane 300mL is stirred, ice-water bath cools down 10 DEG C, nitrogen
It is added under gas shielded and 56g potassium hydroxide (1.0mol) is added portionwise, control system temperature is not higher than 20 DEG C, finishes, and stirs 30min
Dehydrochlorination；2- hydroxyl ethyl acetates 135.3g (1.3mol), drop are added dropwise into reaction system of the gained containing 2-chloroethyl amine
Finish, reacts 9h at room temperature, GC detects 2-chloroethyl amine, and the reaction was complete；Gained system is filtered, will be obtained using 200mL water
Filtrate is washed, and is isolated the water phase in resulting material after washing, is extracted to gained water phase using 100mL dichloromethane
It takes, gained organic phase is dried with anhydrous sodium sulfate, after vacuum distillation removal solvent, obtain 2- (glycolamide base) chloroethene
Alkane.
The 2- (glycolamide base) chloroethanes, tetrahydrofuran 600mL are mixed with potassium tert-butoxide 135g (1.2mol),
It is slowly heated to reflux (65~70 DEG C), gained system is filtered by insulation reaction 15h, and filtrate decompression distillation removal is molten
Agent is heated to reflux 30min and carries out adsorption bleaching, by resulting material after mixing residue with 200mL ethyl acetate, 5g activated carbons
Removal activated carbon and remaining inorganic salts are filtered, gained liquid material are mixed with 200mL petroleum ethers, in 0 DEG C, stirring bar
Recrystallization 6h is carried out under part, a large amount of solids are precipitated, and filters, gained filter cake is dried in vacuo, white powder 3- morpholines are obtained
Ketone 71.6g, yield 70.9%, purity 99.3%；Fusing point is 97~99 DEG C.
1H-NMR(400MHz,CDCl3)δ:7.886(s,1H)；4.098(s,1H)；3.770 (t, J=10.4Hz, 2H)；
3.371~3.357 (m, 2H)；13C-NMR(100MHz,CDCl3):δ:169.488；67.583；63.093；41.094；IR
(neat)1667,1347,1120,799cm-1。
As seen from the above embodiment, method and process side reaction provided by the invention is few, is convenient for product purification；Easy to operate,
It is safe, environmental-friendly；Raw material are easy to get, are cheap；Product yield high (up to 75.5%), purity it is high (up to 99% with
On), it is suitable for industrialized mass production, there is good industrial prospect.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of 3- morpholones, includes the following steps：
(1) dehydrohalogenation under the conditions of by the halogenated ethamine halogen acid salts of 2- existing for organic solvent, by gained reaction system with
Amine ester exchange reaction is carried out after the mixing of 2- glycolic acid esters, obtains 2- (glycolamide base) halogen ethane；
(2) under the conditions of by 2- (glycolamide base) halogen ethane in the step (1) existing for base reagent and organic solvent
Ring closure reaction is carried out, 3- morpholones are obtained.
2. preparation method according to claim 1, which is characterized in that the halogenated ethamine halogen acid salts of 2- in the step (1)
Molar ratio with 2- glycolic acid esters is 1：(1~3).
3. preparation method according to claim 1 or 2, which is characterized in that the halogenated ethamine halogen acids of 2- in the step (1)
Salt includes 2-chloroethyl amine hydrochloride or 2- bromine ethylamine hydrobromides.
4. preparation method according to claim 1 or 2, which is characterized in that 2- glycolic acid esters include in the step (1)
2- hydroxy methyl acetates, 2- hydroxyl ethyl acetates, 2- hydroxyacetic acids n-propyl or 2- hydroxyacetic acid isopropyl esters.
5. preparation method according to claim 1, which is characterized in that the temperature of amine ester exchange reaction in the step (1)
It it is -10~50 DEG C, the time is 8~10h.
6. preparation method according to claim 1, which is characterized in that 2- (glycolamide base) halogen in the step (2)
The molar ratio of ethane and base reagent is 1：(1~3).
7. preparation method according to claim 1 or 6, which is characterized in that in the step (2) base reagent be organic base or
Inorganic base.
8. preparation method according to claim 7, which is characterized in that the organic base includes sodium methoxide, sodium ethoxide, tertiary fourth
Sodium alkoxide, potassium tert-butoxide, tert-butyl alcohol lithium or tert-butyl alcohol magnesium.
9. preparation method according to claim 7, which is characterized in that the inorganic base includes potassium carbonate, sodium carbonate, carbonic acid
Caesium, potassium hydroxide, sodium hydroxide, cesium hydroxide or lithium hydroxide.
10. preparation method according to claim 1, which is characterized in that the temperature of ring closure reaction is 50 in the step (2)
~100 DEG C, the time is 10~30h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU488815A1 (en) * | 1974-06-07 | 1975-10-25 | Пермский фармацевтический институт | Method for preparing 3,3-diaryl-4-chloropyrrolidinone-2 |
| CN101735165A (en) * | 2010-01-19 | 2010-06-16 | 苏州天马精细化学品股份有限公司 | Preparation method of 3-morpholone |
| CN104356086A (en) * | 2014-11-28 | 2015-02-18 | 湖南科技大学 | Preparation method of 3-morpholone suitable for industrial production |
-
2018
- 2018-06-07 CN CN201810581339.3A patent/CN108586377B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU488815A1 (en) * | 1974-06-07 | 1975-10-25 | Пермский фармацевтический институт | Method for preparing 3,3-diaryl-4-chloropyrrolidinone-2 |
| CN101735165A (en) * | 2010-01-19 | 2010-06-16 | 苏州天马精细化学品股份有限公司 | Preparation method of 3-morpholone |
| CN104356086A (en) * | 2014-11-28 | 2015-02-18 | 湖南科技大学 | Preparation method of 3-morpholone suitable for industrial production |
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